DESCRIPTION: This application for renewed support is directed at normal and pathological functional arrangements associated with primary afferent neurons with thin fibers, a population known to be of major importance for pain, temperature sense and related reactions. The overall goals are for better fundamental understanding of the underlying neural functioning and to thereby provide improved strategies for pain management. The proposed work focuses upon two issues. 1) one phase of the work deals with the nature of interconnections among neurons of the superficial dorsal horn (SDH), the region receiving a principal input from the thin, largely nocireceptive, primary afferent fibers. The aim for this phase of the work is to determine the nature of synaptic connections between neurons of the region and the relationship of these connections to input from the primary afferent fibers. The experiments will be done in vitro on spinal cord slices with attached dorsal roots acutely prepared from purpose-bred rodents (hamster, rat). Whole cell, tight-seal recordings are to be used to obtain low noise recording from one or simultaneously from two SDH neurons to study interactions between activity produced by primary afferent fibers, by focal SDH stimuli and by the neurons themselves. The experiments will also explore the importance of purine agents such as ATP and adenosine as synaptic mediators between neural elements of this part of the spinal cord as evidenced by the action of selective pharmacological antagonists and agonists. 2) A second project is directed at processes associated with the novel development of sympathetic adrenergic excitation by cutaneous nociceptors after partial nerve injury and the influence of neurotrophins or other cytokines on them. The latter experiments involve in vitro whole-cell recordings from DRG neurons I) acutely dissociated and cultured from adult purpose-bred rats, ii) acutely dissociated from adult rats with prior nerve injury and iii) dissociated from immature rats at several stages during development. Chemically-defined media will be used for culture to permit the addition or removal of factors possibly influencing the expression of the excitatory adrenergic action.